{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:23:50Z","timestamp":1789662230775,"version":"4.0.1"},"reference-count":132,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Federation Fundamental Research Program","award":["122022800499-5"],"award-info":[{"award-number":["122022800499-5"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>L-asparaginase (L-ASNase) is a key therapeutic enzyme used in the treatment of acute lymphoblastic leukemia and other hematological malignancies. However, its clinical application is limited by a short plasma half-life, significant toxicity, and immunogenicity. To address these limitations, various strategies have been developed, including conjugation of the enzyme with polyethylene glycol and the use of enzymes from alternative sources with lower immunogenicity. Nevertheless, effective targeting of tumor cells, particularly in solid tumors, remains a major challenge. Protein fusion technology has emerged as a promising approach to improve the pharmacological properties of L-asparaginase by enhancing stability, prolonging circulation time, enabling targeted delivery, and integrating multiple functional domains into a single construct, thereby addressing several limitations simultaneously. This review analyzes current strategies for the design of L-asparaginase-based fusion proteins, including the fusion of protein domains to improve pharmacokinetics and the fusion of targeting peptides or proteins to enhance local cytotoxicity. A comparative analysis indicates that elastin-like peptide (ELP)-based constructs primarily enhance the half-life of L-ASNase, whereas albumin-binding domain (ABD)- and heparin-binding domain (HBD)-based fusions provide more pronounced improvements in both half-life extension and in vivo efficacy. However, described strategies require further validation to ensure enhanced selectivity. Overall, fusion protein technology represents a promising avenue for the development of next-generation L-asparaginase therapeutics.<\/jats:p>","DOI":"10.3390\/biom16070963","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fusion Protein Technology to Enhance Pharmacological Properties of L-Asparaginases"],"prefix":"10.3390","volume":"16","author":[{"given":"Anastasiya N.","family":"Shishparenok","sequence":"first","affiliation":[{"name":"Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, 10\/7 Pogodinskaya St., 119121 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3290-9839","authenticated-orcid":false,"given":"Varvara G.","family":"Blinova","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, 10\/7 Pogodinskaya St., 119121 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4753-7588","authenticated-orcid":false,"given":"Dmitry D.","family":"Zhdanov","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, 10\/7 Pogodinskaya St., 119121 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Jadhav, R.S., Sharma, H., and Kulshrestha, S. (2026). Applications and Scope of Microbial L-Asparaginase. Pharmaceutically Relevant Microbial Enzymes, Springer Nature.","DOI":"10.1007\/978-981-95-4941-2_9"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Deng, L., Zhou, J., Liu, Y., and Cui, H. (2026). Mechanistic insights into L-asparaginase resistance in cancers. Cell. Signal., 139.","DOI":"10.1016\/j.cellsig.2025.112317"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tripathy, R.K., Anakha, J., and Pande, A.H. (2024). Towards development of biobetter: L-asparaginase a case study. Biochim. Biophys. Acta-Gen. Subj., 1868.","DOI":"10.1016\/j.bbagen.2023.130499"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pagliaro, L., Chen, S.-J., Herranz, D., Mecucci, C., Harrison, C.J., Mullighan, C.G., Zhang, M., Chen, Z., Boissel, N., and Winter, S.S. (2024). Acute lymphoblastic leukaemia. Nat. Rev. Dis. Prim., 10.","DOI":"10.1038\/s41572-024-00525-x"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pokrovskaya, M.V., Pokrovsky, V.S., Aleksandrova, S.S., Sokolov, N.N., and Zhdanov, D.D. (2022). Molecular Analysis of L-Asparaginases for Clarification of the Mechanism of Action and Optimization of Pharmacological Functions. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030599"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s12223-022-00952-x","article-title":"Characterization of novel L-asparaginases having clinically safe profiles from bacteria inhabiting the hemolymph of the crab, Scylla serrata (Forsk\u00e5l, 1775)","volume":"67","author":"Lailaja","year":"2022","journal-title":"Folia Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Shishparenok, A.N., Gladilina, Y.A., Pokrovskaya, M.V., Aleksandrova, S.S., Kraevsky, S.V., Ivanov, Y.D., Kozlov, A.F., Zlotnikov, I.D., Kudryashova, E.V., and Atroshenko, D.L. (2026). Immobilization of l-asparaginase on oxidized bacterial cellulose to enhance stability and cytotoxic activity. Int. J. Biol. Macromol., 339.","DOI":"10.1016\/j.ijbiomac.2025.149992"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Schnuchel, A., Radcke, C., Theobald, L., and Doeding, S. (2023). Quality comparison of a state-of-the-art preparation of a recombinant L-asparaginase derived from Escherichia coli with an alternative asparaginase product. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0285948"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1042\/BA20030138","article-title":"One-step purification and kinetic properties of the recombinant l-asparaginase from Erwinia carotovora","volume":"39","author":"Krasotkina","year":"2004","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_10","first-page":"175","article-title":"Mechanisms of Development of Side Effects and Drug Resistance to Asparaginase and Ways to Overcome Them","volume":"16","author":"Alexandrova","year":"2022","journal-title":"Biochem. Suppl. Ser. B Biomed. Chem."},{"key":"ref_11","unstructured":"Medac GmbH (2026, June 23). Spectrila. Summary of Product Characteristics. Available online: https:\/\/www.medac.eu\/fileadmin\/user_upload\/medac-eu\/SPCs\/common_SPCs\/Spectrila-spc-EN.pdf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.3109\/10428194.2014.1003056","article-title":"Asparaginase pharmacokinetics and implications of therapeutic drug monitoring","volume":"56","author":"Asselin","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_13","unstructured":"U.S. Food and Drug Administration (2026, June 23). Erwinaze (Asparaginase Erwinia Chrysanthemi) Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/125359s088lbl.pdf."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Meneguetti, G.P., Santos, J.H.P.M., Obreque, K.M.T., Barbosa, C.M.V., Monteiro, G., Farsky, S.H.P., Marim de Oliveira, A., Angeli, C.B., Palmisano, G., and Ventura, S.P.M. (2019). Novel site-specific PEGylated L-asparaginase. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211951"},{"key":"ref_15","unstructured":"European Medicines Agency (2026, June 23). Oncaspar. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/oncaspar."},{"key":"ref_16","unstructured":"(2016). Assessment Report, European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/assessment-report\/oncaspar-epar-public-assessment-report_en.pdf."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.1200\/JCO.2014.55.5763","article-title":"Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children\u2019s Oncology Group Study AALL07P4","volume":"32","author":"Angiolillo","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/bab.1723","article-title":"Production of a novel N-terminal PEGylated crisantaspase","volume":"66","author":"Meneguetti","year":"2019","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ebrahimi, S.B., and Samanta, D. (2023). Engineering protein-based therapeutics through structural and chemical design. Nat. Commun., 14.","DOI":"10.1038\/s41467-023-38039-x"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liang, S., Deng, X., and Liu, X. (2026). Long-circulating protein-polymer conjugates: Advancing beyond PEGylated proteins. Nano Res., 19.","DOI":"10.26599\/NR.2026.94908529"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1080\/14796694.2024.2395235","article-title":"CASPER: A Phase I trial combining calaspargase pegol-mnkl and cobimetinib in pancreatic cancer","volume":"20","author":"Lopez","year":"2024","journal-title":"Future Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Van Trimpont, M., Peeters, E., De Visser, Y., Schalk, A.M., Mondelaers, V., De Moerloose, B., Lavie, A., Lammens, T., Goossens, S., and Van Vlierberghe, P. (2022). Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy. Cancers, 14.","DOI":"10.3390\/cancers14040902"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Edwards, W.R., Busse, K., Allemann, R.K., and Jones, D.D. (2008). Linking the functions of unrelated proteins using a novel directed evolution domain insertion method. Nucleic Acids Res., 36.","DOI":"10.1093\/nar\/gkn363"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ma, Y., Zhang, N., Vernet, G., and Kara, S. (2022). Design of fusion enzymes for biocatalytic applications in aqueous and non-aqueous media. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.944226"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1021\/acs.biomac.4c00188","article-title":"Genetic Functionalization of Protein-Based Biomaterials via Protein Fusions","volume":"25","author":"Mendes","year":"2024","journal-title":"Biomacromolecules"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Marsh, M.C., and Owen, S.C. (2023). Therapeutic Fusion Proteins. AAPS J., 26.","DOI":"10.1208\/s12248-023-00873-8"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.oooo.2018.11.012","article-title":"Medication-related osteonecrosis of the jaw unrelated to bisphosphonates and denosumab\u2014A review","volume":"127","author":"King","year":"2019","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.biotechadv.2014.11.005","article-title":"Synthetic fusion protein design and applications","volume":"33","author":"Yu","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Druzhkova, I.N., Orlova, A.G., Fedulova, A.S., Avakiants, A.V., Isakova, A.A., Kukovyakina, E.V., Zijian, Y., Plotnikova, E.A., Trunova, G.V., and Pankratov, A.A. (2025). Multivalent fusion protein targeting VEGFR2 and DR5 receptors: Assessing the antiangiogenic and antitumor effects via multimodal microangiography. J. Transl. Med., 23.","DOI":"10.1186\/s12967-025-06859-8"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wu, Y. (2025). Trends in nanobody technology in industrialization. Discov. Nano, 20.","DOI":"10.1186\/s11671-025-04200-2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/nbt0492-442","article-title":"Monoclonal Antibodies Can Protect L\u2013Asparaginase Against Inactivation by Trypsin","volume":"10","author":"Ramjeesingh","year":"1992","journal-title":"Bio\/Technology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s40264-015-0285-9","article-title":"Chimeric Fusion Proteins Used for Therapy: Indications, Mechanisms, and Safety","volume":"38","author":"Baldo","year":"2015","journal-title":"Drug Saf."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1080\/19420862.2016.1268307","article-title":"The making of bispecific antibodies","volume":"9","author":"Brinkmann","year":"2017","journal-title":"mAbs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.1101\/gad.228544.113","article-title":"Structure and function of Norrin in assembly and activation of a Frizzled 4\u2013Lrp5\/6 complex","volume":"27","author":"Ke","year":"2013","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jmb.2004.03.039","article-title":"Domain Insertions in Protein Structures","volume":"338","author":"Hubbard","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1038\/s41592-025-02741-z","article-title":"Rational engineering of allosteric protein switches by in silico prediction of domain insertion sites","volume":"22","author":"Wolf","year":"2025","journal-title":"Nat. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Li, G., Wang, H., Zhang, X., Wu, Z., and Yang, H. (2021). A Cas9\u2013transcription factor fusion protein enhances homology-directed repair efficiency. J. Biol. Chem., 296.","DOI":"10.1016\/j.jbc.2021.100525"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Coyote-Maestas, W., He, Y., Myers, C.L., and Schmidt, D. (2019). Domain insertion permissibility-guided engineering of allostery in ion channels. Nat. Commun., 10.","DOI":"10.1038\/s41467-018-08171-0"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Plaper, T., Knez \u0160tibler, U., and Jerala, R. (2025). Synthetic Biology for Designing Allostery and Its Potential Biomedical Applications. J. Mol. Biol., 437.","DOI":"10.1016\/j.jmb.2025.169225"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Plaper, T., Merljak, E., Fink, T., Satler, T., Ljubeti\u010d, A., Lain\u0161\u010dek, D., Jazbec, V., Ben\u010dina, M., Stevanoska, S., and D\u017eeroski, S. (2024). Designed allosteric protein logic. Cell Discov., 10.","DOI":"10.1038\/s41421-023-00635-y"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1021\/acs.bioconjchem.3c00357","article-title":"Rapid Access to Potent Bispecific T Cell Engagers Using Biogenic Tyrosine Click Chemistry","volume":"34","author":"Shajan","year":"2023","journal-title":"Bioconjug. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Sornay, C., Vaur, V., Wagner, A., and Chaubet, G. (2022). An overview of chemo- and site-selectivity aspects in the chemical conjugation of proteins. R. Soc. Open Sci., 9.","DOI":"10.1098\/rsos.211563"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14404","DOI":"10.1021\/jacs.2c00129","article-title":"Chemical and Enzymatic Methods for Post-Translational Protein\u2013Protein Conjugation","volume":"144","author":"Taylor","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00253-012-4569-z","article-title":"Enzyme-catalyzed protein crosslinking","volume":"97","author":"Heck","year":"2013","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.1073\/pnas.101064198","article-title":"Structure of sortase, the transpeptidase that anchors proteins to the cell wall of Staphylococcus aureus","volume":"98","author":"Ilangovan","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16839","DOI":"10.1021\/acs.iecr.1c02842","article-title":"Optimized Production of Fc Fusion Proteins by Sortase Enzymatic Ligation","volume":"60","author":"Apley","year":"2021","journal-title":"Ind. Eng. Chem. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kumar, H., and Kim, P. (2024). Artificial intelligence in fusion protein three-dimensional structure prediction: Review and perspective. Clin. Transl. Med., 14.","DOI":"10.1002\/ctm2.1789"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Shafique, Q.U.A., Rehman, H.M., Zaheer, T., Tahir, R.A., Bhinder, M.A., Gul, R., and Saleem, M. (2021). A Computational Approach to Modeling an Antagonistic Angiogenic VEGFR1-IL2 Fusion Protein for Cancer Therapy. Bioinform. Biol. Insights, 15.","DOI":"10.1177\/11779322211043297"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Muhammad Rehman, H., Rehman, H.M., Naveed, M., Khan, M.T., Shabbir, M.A., Aslam, S., and Bashir, H. (2023). In Silico Investigation of a Chimeric IL24-LK6 Fusion Protein as a Potent Candidate Against Breast Cancer. Bioinform. Biol. Insights, 17.","DOI":"10.1177\/11779322231182560"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Rehman, H.M., Yousaf, N., Hina, S.M., Nadeem, T., Ansari, M.A., Chaudry, A., Kafait, I., Khalid, S., Alanzi, A.R., and Bashir, H. (2024). Design and computational analysis of a novel Azurin-BR2 chimeric protein against breast cancer. Toxicol. Res., 13.","DOI":"10.1093\/toxres\/tfae179"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"159","DOI":"10.4103\/1735-5362.367795","article-title":"A comparative study of the arazyme-based fusion proteins with various ligands for more effective targeting cancer therapy","volume":"18","author":"Mehrab","year":"2023","journal-title":"Res. Pharm. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hashemi Yeganeh, H., Heiat, M., Kieliszek, M., Alavian, S.M., and Rezaie, E. (2021). DT389-YP7, a Recombinant Immunotoxin against Glypican-3 That Inhibits Hepatocellular Cancer Cells: An In Vitro Study. Toxins, 13.","DOI":"10.3390\/toxins13110749"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bala, S., Shinya, S., Srivastava, A., Ishikawa, M., Shimada, A., Kobayashi, N., Kojima, C., Tama, F., Miyashita, O., and Kohda, D. (2020). Crystal contact-free conformation of an intrinsically flexible loop in protein crystal: Tim21 as the case study. Biochim. Biophys. Acta-Gen. Subj., 1864.","DOI":"10.1016\/j.bbagen.2019.129418"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1021\/mp200347q","article-title":"Balancing the Pharmacokinetics and Pharmacodynamics of Interferon-\u03b12b and Human Serum Albumin Fusion Protein by Proteolytic or Reductive Cleavage Increases Its in Vivo Therapeutic Efficacy","volume":"9","author":"Zhao","year":"2012","journal-title":"Mol. Pharm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.addr.2012.09.039","article-title":"Fusion protein linkers: Property, design and functionality","volume":"65","author":"Chen","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1158\/2326-6066.CIR-22-0504","article-title":"Rational Protein Design Yields a CD20 CAR with Superior Antitumor Efficacy Compared with CD19 CAR","volume":"11","author":"Chen","year":"2023","journal-title":"Cancer Immunol. Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Charlton, A. (2008). Site-Specific Cleavage of Fusion Proteins. Affinity Chromatography, Humana Press.","DOI":"10.1007\/978-1-59745-582-4_14"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Schmidt, S.R. (2024). Fusion Proteins: Current Status and Future Perspectives. Bioprocessing, Bioengineering and Process Chemistry in the Biopharmaceutical Industry, Springer Nature.","DOI":"10.1007\/978-3-031-62007-2_11"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1080\/19420862.2015.1019788","article-title":"Fusion protein technologies for biopharmaceuticals: Applications and challenges","volume":"7","author":"Berger","year":"2015","journal-title":"MAbs"},{"key":"ref_60","first-page":"284","article-title":"Fusion-proteins as biopharmaceuticals\u2014Applications and challenges","volume":"12","author":"Schmidt","year":"2009","journal-title":"Curr. Opin. Drug Discov. Devel."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s40259-015-0133-6","article-title":"Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters","volume":"29","author":"Strohl","year":"2015","journal-title":"BioDrugs"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3109\/07388551.2013.834293","article-title":"Fc-fusion proteins and FcRn: Structural insights for longer-lasting and more effective therapeutics","volume":"35","author":"Rath","year":"2015","journal-title":"Crit. Rev. Biotechnol."},{"key":"ref_63","unstructured":"Tianjin SinoBiotech Ltd (2021). Study of Recombinant Human Serum Albumin\/Interferon alpha2b Fusion Protein in Hepatitis B Patient."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s13273-019-0040-x","article-title":"Application of therapeutic protein-based fusion toxins","volume":"15","author":"Ahn","year":"2019","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mahmoudi, R., Dianat-Moghadam, H., Poorebrahim, M., Siapoush, S., Poortahmasebi, V., Salahlou, R., and Rahmati, M. (2021). Recombinant immunotoxins development for HER2-based targeted cancer therapies. Cancer Cell Int., 21.","DOI":"10.1186\/s12935-021-02182-6"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Cheung, L.H., Zhao, Y., Alvarez-Cienfuegos, A., Mohamedali, K.A., Cao, Y.J., Hittelman, W.N., and Rosenblum, M.G. (2019). Development of a human immuno-oncology therapeutic agent targeting HER2: Targeted delivery of granzyme B. J. Exp. Clin. Cancer Res., 38.","DOI":"10.1186\/s13046-019-1333-6"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.2174\/138161209788923877","article-title":"Immunokinases, a Novel Class of Immunotherapeutics for Targeted Cancer Therapy","volume":"15","author":"Tur","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1158\/1535-7163.MCT-15-0685","article-title":"A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells","volume":"15","author":"Lilienthal","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_69","unstructured":"Pedley, R.B., Sharma, S.K., Hawkins, R.E., and Chester, K.A. (2004). Antibody-Directed Enzyme-Prodrug Therapy. Suicide Gene Therapy, Humana Press."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/sj.bjc.6600517","article-title":"A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours","volume":"87","author":"Francis","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"717","DOI":"10.6004\/jadpro.2022.13.7.8","article-title":"Tebentafusp-tebn: A Novel Bispecific T-Cell Engager for Metastatic Uveal Melanoma","volume":"13","author":"Hwa","year":"2022","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Quan, G., Liu, Y., Wang, Z., Shi, N., Wu, Y., Liu, Q., Gao, X., Zhang, R., and Luo, L. (2023). Anti-Claudin18.2-IL-21 fusion protein bifunctional molecule has more powerful anti-tumor effect and better safety. Int. Immunopharmacol., 115.","DOI":"10.1016\/j.intimp.2022.109634"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Huang, K., Duan, N., Zhang, C., Mo, R., and Hua, Z. (2017). Improved antitumor activity of TRAIL fusion protein via formation of self-assembling nanoparticle. Sci. Rep., 7.","DOI":"10.1038\/srep41904"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Wang, Y., Qian, X., Wang, Y., Yu, C., Feng, L., Zheng, X., Wang, Y., and Gong, Q. (2025). Turn TRAIL Into Better Anticancer Therapeutic Through TRAIL Fusion Proteins. Cancer Med., 14.","DOI":"10.1002\/cam4.70517"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Dinca, A., Chien, W.-M., and Chin, M. (2016). Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17020263"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Hasannejad-Asl, B., Pooresmaeil, F., Takamoli, S., Dabiri, M., and Bolhassani, A. (2022). Cell penetrating peptide: A potent delivery system in vaccine development. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2022.1072685"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"32108","DOI":"10.1074\/jbc.M109.032714","article-title":"Targeting Human Epidermal Growth Factor Receptor Signaling with the Neuregulin\u2019s Heparin-binding Domain","volume":"284","author":"Ma","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s40259-023-00622-5","article-title":"Enzyme Engineering Strategies for the Bioenhancement of l-Asparaginase Used as a Biopharmaceutical","volume":"37","author":"Miranda","year":"2023","journal-title":"BioDrugs"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1021\/acs.bioconjchem.7b00217","article-title":"Immobilization of L-Asparaginase on Carrier Materials: A Comprehensive Review","volume":"28","author":"Ulu","year":"2017","journal-title":"Bioconjug. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Sonowal, S., Pathak, K., Das, D., Buragohain, K., Gogoi, A., Borah, N., Das, A., and Nath, R. (2024). L-Asparaginase Bio-Betters: Insight Into Current Formulations, Optimization Strategies and Future Bioengineering Frontiers in Anti-Cancer Drug Development. Adv. Ther., 7.","DOI":"10.1002\/adtp.202400156"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Jia, R., Wan, X., Geng, X., Xue, D., Xie, Z., and Chen, C. (2021). Microbial L-asparaginase for Application in Acrylamide Mitigation from Food: Current Research Status and Future Perspectives. Microorganisms, 9.","DOI":"10.3390\/microorganisms9081659"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"K\u00f6ppl, C., Lingg, N., Fischer, A., Kr\u00f6\u00df, C., Loibl, J., Buchinger, W., Schneider, R., Jungbauer, A., Striedner, G., and Cserjan-Puschmann, M. (2022). Fusion Tag Design Influences Soluble Recombinant Protein Production in Escherichia coli. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147678"},{"key":"ref_83","unstructured":"Lavie, A., Nguyen, H.-A., and Su, Y. (2017). L-Asparaginase Variants and Fusion Proteins with Reduced L-Glutaminase Activity and Enhanced Stability."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"675","DOI":"10.34172\/apb.2024.048","article-title":"Investigating Functional and Folding Stability of an Engineered E. coli L-asparaginase Harboring Y176F\/S241C Mutations","volume":"14","author":"Dastmalchi","year":"2024","journal-title":"Adv. Pharm. Bull."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Shishparenok, A.N., Gladilina, Y.A., and Zhdanov, D.D. (2023). Engineering and Expression Strategies for Optimization of L-Asparaginase Development and Production. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015220"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Arakawa, T., and Akuta, T. (2025). Beyond Purification: Evolving Roles of Fusion Tags in Biotechnology. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47090768"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.32604\/or.2025.062197","article-title":"Unlocking the potential of tumor-targeting peptides in precision oncology","volume":"33","author":"Rehman","year":"2025","journal-title":"Oncol. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.tips.2021.09.009","article-title":"Engineered antibody fusion proteins for targeted disease therapy","volume":"42","author":"Silver","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.nbt.2019.04.002","article-title":"Antibody-cytokine fusion proteins: A novel class of biopharmaceuticals for the therapy of cancer and of chronic inflammation","volume":"52","author":"Murer","year":"2019","journal-title":"New Biotechnol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Ghaderi, H., Alipour, A., Mohammadi Zadeh Holagh, A., Lomedasht, F.K., Abdollahpour-Alitappeh, M., Kaghazian, H., and Shahsavarani, H. (2023). Recombinant antibody fragment therapeutics: Current status and future prospects of scFv, nanobody, and mimotopes. J. Drug Deliv. Sci. Technol., 89.","DOI":"10.1016\/j.jddst.2023.105009"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/0141-0229(95)91162-R","article-title":"Engineering resistance to trypsin inactivation into L-asparaginase through the production of a chimeric protein between the enzyme and a protective single-chain antibody","volume":"17","author":"Newsted","year":"1995","journal-title":"Enzym. Microb. Technol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1042\/BA19990062","article-title":"Selecting and expressing protective single-chain Fv fragment to stabilize L-asparaginase against inactivation by trypsin","volume":"31","author":"Guo","year":"2000","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1006\/bbrc.2000.3434","article-title":"Characterization of -Asparaginase Fused with a Protective ScFv and the Protection Mechanism","volume":"276","author":"Guo","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Babamohamadi, M., Mohammadi, N., Faryadi, E., Haddadi, M., Merati, A., Ghobadinezhad, F., Amirian, R., Izadi, Z., and Hadjati, J. (2024). Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy. Cell Death Dis., 15.","DOI":"10.1038\/s41419-023-06391-x"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Maggi, M., Pessino, G., Guardamagna, I., Lonati, L., Pulimeno, C., and Scotti, C. (2021). A Targeted Catalytic Nanobody (T-CAN) with Asparaginolytic Activity. Cancers, 13.","DOI":"10.3390\/cancers13225637"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"409","DOI":"10.3324\/haematol.2022.281390","article-title":"In vivo stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia","volume":"108","author":"Schalk","year":"2022","journal-title":"Haematologica"},{"key":"ref_97","unstructured":"Leung, Y.-C., Wong, K.-Y., Tam, S.-Y., and Chung, S.-F. (2025). Bioengineered Asparaginase Fusion Proteins."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Beeton, K., Mitra, D., Akinleye, A.A., Howell, J.A., Yu, C.S., Bidwell, G.L., and Tandon, R. (2024). An Elastin-like Polypeptide-fusion peptide targeting capsid-tegument interface as an antiviral against cytomegalovirus infection. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-60691-6"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1039\/C8BM01096J","article-title":"One-month zero-order sustained release and tumor eradication after a single subcutaneous injection of interferon alpha fused with a body-temperature-responsive polypeptide","volume":"7","author":"Wang","year":"2019","journal-title":"Biomater. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Zhang, S., Sun, Y., Zhang, L., Zhang, F., and Gao, W. (2023). Thermoresponsive Polypeptide Fused L-Asparaginase with Mitigated Immunogenicity and Enhanced Efficacy in Treating Hematologic Malignancies. Adv. Sci., 10.","DOI":"10.1002\/advs.202300469"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jconrel.2019.02.016","article-title":"Current strategies in extending half-lives of therapeutic proteins","volume":"301","author":"Zaman","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Zhang, S., Gong, L., Sun, Y., Zhang, F., and Gao, W. (2025). An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors. Biomaterials, 312.","DOI":"10.1016\/j.biomaterials.2024.122740"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2174\/092986606775101689","article-title":"Asparaginase Display of Human Cholesteryl Ester Transfer Protein (CETP) B Cell Epitopes for Inducing High Titers of Anti-CETP Antibodies In Vivo","volume":"13","author":"Gaofu","year":"2006","journal-title":"Protein Pept. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Rigouin, C., Nguyen, H.A., Schalk, A.M., and Lavie, A. (2017). Discovery of human-like L-asparaginases with potential clinical use by directed evolution. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-10758-4"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"16333","DOI":"10.1021\/acsomega.5c12075","article-title":"Expression, Solubilization, and Refolding Recovery of a Novel L-Asparaginase\u2013Arginase 1 Chimera from E. coli Inclusion Bodies","volume":"11","author":"Rivera","year":"2026","journal-title":"ACS Omega"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/S0161-5890(97)00144-2","article-title":"Construction and characterisation of a functional CD19 specific single chain Fv fragment for immunotherapy of B lineage leukaemia and lymphoma","volume":"34","author":"Nicholson","year":"1997","journal-title":"Mol. Immunol."},{"key":"ref_107","unstructured":"Maggi, M., Pessino, G., and Scotti, C. (2020). An Antibody Drug Fusion Based on Asparaginase. (WIPO Patent WO2020058749A1)."},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Mu\u00f1oz-Alarc\u00f3n, A., Helmfors, H., Karlsson, K., and Langel, \u00dc. (2013). Cell-Penetrating Peptide Fusion Proteins. Fusion Protein Technologies for Biopharmaceuticals, Wiley.","DOI":"10.1002\/9781118354599.ch26"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"9127","DOI":"10.1016\/j.biomaterials.2012.08.063","article-title":"A protein delivery system using 30Kc19 cell-penetrating protein originating from silkworm","volume":"33","author":"Park","year":"2012","journal-title":"Biomaterials"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1080\/21691401.2022.2126851","article-title":"Enhanced anti-cancer effect using MMP-responsive L-asparaginase fused with cell-penetrating 30Kc19 protein","volume":"50","author":"Ryu","year":"2022","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.jconrel.2008.06.017","article-title":"PTD-modified ATTEMPTS system for enhanced asparaginase therapy: A proof-of-concept investigation","volume":"130","author":"Kwon","year":"2008","journal-title":"J. Control. Release"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1007\/s12033-016-9950-1","article-title":"The Modified Heparin-Binding L-Asparaginase of Wolinella succinogenes","volume":"58","author":"Sannikova","year":"2016","journal-title":"Mol. Biotechnol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"33512","DOI":"10.18632\/oncotarget.9257","article-title":"Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo","volume":"7","author":"Ramani","year":"2016","journal-title":"Oncotarget"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Mazloum-Ravasan, S., and Hamishehkar, H. (2026). Recent progress on the development of nanoparticulate L-asparaginase for enhanced anti-cancer activity. Cancer Nanotechnol., 17.","DOI":"10.1186\/s12645-026-00364-3"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Santelli, J., Heble, A.Y., Endsley, C., Woodward, A., Hafeez, N., Winick, N., and Lux, J. (2026). An Integrated Method to Evaluate the Treatment Efficacy and Immunogenicity of B-Cell Acute Lymphoblastic Leukemia Therapeutic Enzyme Formulations. Small Methods, 10.","DOI":"10.1002\/smtd.202500945"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s10637-014-0102-9","article-title":"Pharmacology, immunogenicity, and efficacy of a novel pegylated recombinant Erwinia chrysanthemi-derived L-asparaginase","volume":"32","author":"Chien","year":"2014","journal-title":"Investig. New Drugs"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/bjc.2014.425","article-title":"Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts","volume":"111","author":"Chiu","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1097\/MPA.0b013e318247d903","article-title":"Pancreatic Tumor Sensitivity to Plasma L-Asparagine Starvation","volume":"41","author":"Dufour","year":"2012","journal-title":"Pancreas"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Van Trimpont, M., Schalk, A.M., Hofkens, K., Peeters, E., T\u2019Sas, S., Vandemeulebroecke, K., Su, Y., De Loera, A., Garcia, A., and Chen, H. (2025). A human-like glutaminase-free asparaginase is highly efficacious in ASNSlow leukemia and solid cancer mouse xenograft models. Cancer Lett., 611.","DOI":"10.1016\/j.canlet.2024.217404"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Shen, Y., Wang, H., Guo, D., Liu, J., Sun, J., Chen, N., Song, H., and Ji, X. (2025). Dual asparagine-depriving nanoparticles against solid tumors. Nat. Commun., 16.","DOI":"10.1038\/s41467-025-60798-y"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Yuan, Q., Yin, L., He, J., Zeng, Q., Liang, Y., Shen, Y., and Zu, X. (2024). Metabolism of asparagine in the physiological state and cancer. Cell Commun. Signal., 22.","DOI":"10.1186\/s12964-024-01540-x"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Lefin, N., Miranda, J., Beltr\u00e1n, J.F., Bel\u00e9n, L.H., Effer, B., Pessoa, A., Farias, J.G., and Zamorano, M. (2023). Current state of molecular and metabolic strategies for the improvement of L-asparaginase expression in heterologous systems. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1208277"},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Pokrovsky, V.S., Kazanov, M.D., Dyakov, I.N., Pokrovskaya, M.V., and Aleksandrova, S.S. (2016). Comparative immunogenicity and structural analysis of epitopes of different bacterial L-asparaginases. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2125-4"},{"key":"ref_124","first-page":"1614","article-title":"Rational engineering of L-asparaginase reveals importance of dual activity for cancer cell toxicity","volume":"117","author":"Offman","year":"2011","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Pedroso, A., Herrera Bel\u00e9n, L., Beltr\u00e1n, J.F., Castillo, R.L., Pessoa, A., Pedroso, E., and Far\u00edas, J.G. (2023). In Silico Design of a Chimeric Humanized L-asparaginase. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202301.0537.v1"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Aussel, A., Nemazanyy, I., Vandenberghe, A., Meola, P., Dorat, N., Paul, R., Habbouche, L., Exposito, L., Nottet, N., and Petrilli, V. (2026). Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1\/2 inhibitor in B-cell lymphomas. Nat. Commun., 17.","DOI":"10.1038\/s41467-026-70066-2"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.1016\/j.ymthe.2025.08.019","article-title":"Asparaginase enhances CAR-T cell antitumor immunity by asparagine metabolic reprogramming and central memory induction in ALL","volume":"33","author":"Zhu","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Jiang, J., Batra, S., and Zhang, J. (2021). Asparagine: A Metabolite to Be Targeted in Cancers. Metabolites, 11.","DOI":"10.3390\/metabo11060402"},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Gopalakrishnan, R., Kannan, K., Gunasekaran, R., Ramachandran, P., Ganapathy, D., and Sivaperumal, P. (2025). Marine-derived L-asparaginase: Unlocking marine power in anti-tumor therapeutics. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1710780"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Shen, X., Jain, A., Aladelokun, O., Yan, H., Gilbride, A., Ferrucci, L.M., Lu, L., Khan, S.A., and Johnson, C.H. (2022). Asparagine, colorectal cancer, and the role of sex, genes, microbes, and diet: A narrative review. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.958666"},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Pathria, G., Verma, S., Yin, J., Scott, D.A., and Ronai, Z.A. (2021). MAPK signaling regulates c-MYC for melanoma cell adaptation to asparagine restriction. EMBO Rep., 22.","DOI":"10.15252\/embr.202051436"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ccell.2017.12.003","article-title":"Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase","volume":"33","author":"Gwinn","year":"2018","journal-title":"Cancer Cell"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/7\/963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T04:40:27Z","timestamp":1782880827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/7\/963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":132,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biom16070963"],"URL":"https:\/\/doi.org\/10.3390\/biom16070963","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}